This project will use a unique mammalian study system that was developed specifically to answer questions about heritable neuroendocrine variation that contributes combinatorialy to variation in fertility. Human populations hold large amounts of genetic variation from a great many variable genes that affect complex conditions such as infertility or obesity. Many variable alleles make small or environment-dependent contributions to any given physiological trait, many alleles have cost-benefit trade-offs (and so are negative in some ways, but beneficial in others), some alleles have antagonistic pleiotropic effects (being beneficial for one trait with a cost for another trait), and other alleles have complex epistatic interactions. Recent reviews state that alleles for infertility that have been discovered in men account for a small proportion of cases of infertility. Recent theoretical studies explain why this is expected for such alleles, even in large DNA-sequence studies. Despite these poor results, most studies of heritable causes of infertility continue to be DNA sequence studies. An alternative is to use natural populations to identify and test heritable variation in physiological traits that contribute to fertility and infertility. In my laboratory over the past 15 years, two artificial selection lines from a natural population of white-footed mice (Peromyscus leucopus) have been developed to be either fertile or infertile, respectively, in one environment (short winter-like photoperiod, SD), but fully fertile in another environment (long photoperiod, LD). The selection lines vary heritably and substantially in three neuroendocrine traits that are important regulators of the mammalian reproductive system. The lines also vary heritably in food intake and metabolism, which are known to affect the reproductive system. In this proposal, measurements of values for these traits in a large sample of individuals from an unselected Control line of mice will be used to test for combinatorial contributions of these traits to male fertility and infertility, along with predicted genes-by-environment interactions with photoperiod (SD vs. LD). Additional experiments will test additional, potentially variable neuroendocrine traits to add to an explanatory general linear model for variation in fertility. This proposal is a novel alternative to current research. This study is possible only because of this unique mammalian study system. Success in this project will begin to explain how combinatorial heritable variation from neuroendocrine traits might contribute to infertility in humans. It may be both simpler and more effective to diagnose and treat male infertility using neuroendocrine predictors in mathematical models of combinatorial neuroendocrine variation. PUBLIC HEALTH RELEVANCE: This project investigates how heritable variation in multiple traits of the brain, pituitary, and testes combine to cause impaired fertility or infertility in males. A novel experimental system of white-footed mice was developed in order to identify heritable variation in brain, behavior, and hormonal traits related to fertility. This project is intended to help us understand the 30% of cases of male infertility that have no known causes, and to direct future research into infertility.